TY - JOUR
T1 - Inhibition of the nuclear export receptor XPO1 as a therapeutic target for platinum-resistant ovarian cancer
AU - Chen, Ying
AU - Camacho, Sandra Catalina
AU - Silvers, Thomas R.
AU - Razak, Albiruni R.A.
AU - Gabrail, Nashat Y.
AU - Gerecitano, John F.
AU - Kalir, Eva
AU - Pereira, Elena
AU - Evans, Brad R.
AU - Ramus, Susan J.
AU - Huang, Fei
AU - Priedigkeit, Nolan
AU - Rodriguez, Estefania
AU - Donovan, Michael
AU - Khan, Faisal
AU - Kalir, Tamara
AU - Sebra, Robert
AU - Uzilov, Andrew
AU - Chen, Rong
AU - Sinha, Rileen
AU - Halpert, Richard
AU - Billaud, Jean Noel
AU - Shacham, Sharon
AU - McCauley, Dilara
AU - Landesman, Yosef
AU - Rashal, Tami
AU - Kauffman, Michael
AU - Mirza, Mansoor R.
AU - Mau-Sørensen, Morten
AU - Dottino, Peter
AU - Martignetti, John A.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/3/15
Y1 - 2017/3/15
N2 - Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer. Experimental Design:XPO1expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor. Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor-mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all. Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer.
AB - Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer. Experimental Design:XPO1expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor. Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor-mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all. Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer.
UR - http://www.scopus.com/inward/record.url?scp=85016137128&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-16-1333
DO - 10.1158/1078-0432.CCR-16-1333
M3 - Article
C2 - 27649553
AN - SCOPUS:85016137128
SN - 1078-0432
VL - 23
SP - 1552
EP - 1563
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -